Use of selective ligands for treatment of disease states responsive to steroid or steroid-like retinoids

ABSTRACT

In accordance with the present invention, there is provided a method for the treatment of subjects afflicted with steroid or steroid-like hormone-responsive disease states. The invention method comprises administering to the subject an effective amount of a ligand which selectively interacts with the receptor subtype associated with the steroid or steroid-like hormone-responsive disease state, wherein said ligand interacts with said receptor subtype to a significantly greater extent than with other subtypes of the same receptor class.

RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.08/193,146, filed Feb. 14, 1994, now abandoned, which is in turn a 371of PCT/US92/07064, filed Aug. 21, 1992, published as WO93/03713, Mar. 4,1993, which is a continuation-in-part application of U.S. Ser. No.07/748,767, filed Aug. 23, 1991, now abandoned, the entire contents ofeach of which are hereby incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to therapeutic uses of compounds whichfunction as steroid hormones or steroid-like hormones. In a particularaspect, the present invention relates to the use of compounds whichselectively or preferentially interact with a single subtype of a givensteroid hormone or steroid-like hormone receptor class.

BACKGROUND OF THE INVENTION

Many disease states are consistently associated with the occurrence ofkaryotypic change, e.g., a chromosomal translocation. For example, whenthe gene encoding PML (for "promyelocytes") undergoes a translocationwith the retinoic acid receptor-α (RAR-α) (i.e., translocation betweenchromosomes 15 and 17 at the RAR-α and PML loci), the translocation ismanifested as a form of leukemia, acute promyelocytic leukemia (APL).

It is possible, and even likely in many cases, that when translocationoccurs, a gene product not normally subject to hormone expressioncontrol (e.g., PML) may be placed under the control of a hormoneresponsive sequence (e.g., RAR-α). Thus a gene such as PML may fallunder the control of a hormone responsive sequence (such as RAR-α) as aresult of a translocation event.

It has recently been discovered that APL can be effectively controlledby treatment with retinoic acid. Unfortunately, since several differentreceptors (and subtypes thereof) are known which respond to retinoicacid (e.g., RAR-α, RAR-β, RAR-γ, RXR-α, RXR-β, RXR-γ), administration ofretinoic acid as a treatment for APL has the potential to cause manyundesirable side-reactions for the patient.

There are numerous other disease states which have also been found to beresponsive to treatment with hormones and/or hormone-like compounds. Forexample, Vitamin D-dependent Ricketts is responsive to treatment withVitamin D, acne is responsive to treatment with retinoic acid, and thelike. While available hormone or hormone-like compounds are effectivefor the treatment of such disease states, there is always the competingconcern of undesirable side effects of such hormone treatments.

Accordingly, such disease states can potentially be much moreeffectively treated by using ligands which are selective for thespecific receptor subtype which is involved in the disease state.Indeed, in view of the potential for the use of hormone therapy in thetreatment of many disease states, it would be desirable to have theability to selectively treat subjects with compounds which selectivelyinteract as ligands with the specific receptor subtype involved in thedisease state.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, we have discovered variouscompounds which selectively interact with a single receptor subtype, toa much greater extent than than do other subtypes of the same receptorclass.

Such compounds are useful for the selective treatment of hormoneresponsive disease states, thereby minimizing the occurrence of sideeffects caused by the activation of hormone responsive pathways notdirectly associated with the disease state being treated.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a dose response curve showing the response of RAR-α, RAR-β,RAR-γ, and RXR-α to increasing concentrations of retinoic acid.

FIG. 2 is a dose response curve showing the response of RAR-α, RAR-β,RAR-γ, and RXR-α to increasing concentrations of the phenyl-naphthylderivative referred to herein as Compound I.

FIG. 3 is a dose response curve showing the response of RAR-α, RAR-β,RAR-γ, and RXR-α to increasing concentrations of the polyunsaturatedcarboxylic acid derivative referred to herein as Compound II.

FIG. 4 is a dose response curve showing the response of RAR-α, RAR-β,RAR-γ, and RXR-α to increasing concentrations of the amide derivativereferred to herein as Compound III.

FIG. 5 is a dose response curve showing the response of RAR-α, RAR-β,RAR-γ, and RXR-α to increasing concentrations of the benzophenonederivative referred to herein as Compound IV.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided methods forthe treatment of a subject afflicted with a steroid or steroid-likehormone-responsive disease state, said method comprising administeringto said subject an effective amount of a ligand which selectivelyinteracts with the steroid or steroid-like hormone receptor subtypeassociated with said steroid or steroid-like hormone-responsive diseasestate, wherein said ligand selectively interacts with said steroid orsteroid-like hormone receptor subtype associated with said steroid orsteroid-like hormone-responsive disease state, to a significantlygreater extent than do other subtypes of the same receptor class.

As employed herein, the phrase "steroid or steroid-likehormone-responsive disease state" refers to:

(i) any disease state wherein a gene product (or a portion of a geneproduct) not normally subject to steroid or steroid-like hormoneexpression control is placed, by translocation, under the control of asteroid or steroid-like hormone responsive sequence, or

(ii) any disease state wherein a first gene product (or a portion of agene product) subject to steroid or steroid-like hormone expressioncontrol by a first steroid or steroid-like hormone is placed, bytranslocation, under the control of a second steroid or steroid-likehormone responsive sequence, or

(iii) any disease state which correlates with the expression of abnormalgene product, wherein said gene product (or a portion of said geneproduct) is normally subject to steroid or steroid-like hormoneexpression control, or

(iv) any disease state which correlates with an abnormal level ofexpression of gene product, the expression of which is normallymaintained under steroid or steroid-like hormone expression control, or

(v) any disease state which correlates with an abnormal level ofreceptor, the presence of which is normally maintained under steroid orsteroid-like hormone expression control, or

(vi) any disease state which correlates with an abnormal level ofligand, the presence of which is normally maintained under steroid orsteroid-like hormone expression control.

As employed herein, the phrase "ligand which selectively interacts withthe receptor subtype associated with said steroid or steroid-likehormone responsive disease state to a significantly greater extent thanwith other subtypes of the same receptor class" refers to compoundswhich are preferentially selective for one receptor subtype inmodulating the transcription activation properties thereof. Theterminology "significantly greater extent", as applied to interactionbetween ligand and a specific receptor subtype, refers to ligands whichhave a significantly higher therapeutic index (i.e., the ratio ofefficacy to toxicity) for treatment of the target disease state than foractivation of pathways mediated by other subtypes of the same receptorclass. The toxicity of therapeutic compounds frequently arises from thenon-selective interaction of the therapeutic compound with receptorsubtypes other than the desired receptor subtype. Thus, the presentinvention provides a means to dramatically reduce the incidence ofside-reactions commonly associated with hormone therapy. See, forexample, the selectivity demonstrated in FIGS. 2-5.

It is useful to distinguish the terms receptor "subtype" and receptor"class". For example, retinoid responsive receptors comprise a "class"of receptors, all of which are responsive to retinoid compounds.Similarly, thyroid hormone receptors comprise a "class" of receptorswhich are responsive to thyroid hormone. Each class can be divided intovarious subtypes, i.e., specific members of the class which havedifferent tissue distributions, different affinities for the nativeligand, different activation properties when contacted with the nativeligand, and so on.

Some classes of receptors include sub-families of distinctly differenttypes of receptors. Thus, for example, while the retinoid class ofreceptors includes both the retinoic acid receptors (RARs) and theretinoid X receptors (RXRs), these two different sub-families areclearly distinct. For example, each member of the RAR sub-family isresponsive to a defined first hormone response element (HRE), and eachmember of the RXR sub-family is responsive to a defined second HRE(which is distinctly different from the first HRE). Accordingly, inaccordance with the present invention, there are provided compoundswhich distinguish between the various sub-families of a receptor, and/ordistinguish between the various subtypes thereof.

Ligands contemplated by the present invention are selected from RAR-αselective ligands, RAR-β selective ligands, RAR-γ selective ligands,TR-α-selective ligands, TR-β-selective ligands, RXR-α selective ligands,RXR-β selective ligands, RXR-γ selective ligands, coup-α selectiveligands, coup-β selective ligands, coup-γ selective ligands, and thelike.

Exemplary selective ligands contemplated for use in the practice of thepresent invention include the phenyl-naphthyl derivative having thestructure: ##STR1## referred to herein as Compound I, which selectivelyinteracts with the retinoic acid receptor-β and retinoic acid receptor-γ(see, for example, FIG. 2); the polyunsaturated carboxylic acidderivative having the structure: ##STR2## referred to herein as CompoundII, which selectively interacts with RAR subtypes relative to RXRsubtypes (see, for example, FIG. 3); the amide having the structure:##STR3## referred to herein as Compound III, which selectively interactswith RAR-α, and displays a different rank order of potency relative tothe other RAR subtypes and RXR-α, relative to the other retinoidcompounds tested (see, for example, FIG. 4); the benzophenone derivativehaving the structure: ##STR4## referred to herein as Compound IV, whichselectively interacts with the retinoic acid receptor-β and retinoicacid receptor-α (see, for example, FIG. 5), and the like. These and manyother compounds useful in the practice of the present invention aredescribed in detail in Chemistry and Biology of Synthetic Retinoids,Dawson and Okamura, editors, CRC Press, Inc. (Boca Raton, Fla. 1990),incorporated by reference herein.

The above-described ligands, in suitable form (employing suitablevehicle for delivery, such as, for example, gelatin capsule(s) orcompressed tablet(s) where oral administration is contemplated; in anappropriate base where topical administration is contemplated; in asuitable infusion medium where injection or other means of delivery arecontemplated; and the like), can be administered to a subject employingstandard methods, such as, for example, orally, topically (e.g.,transdermal mode of administration), by intraperitoneal, intramuscular,intravenous, or subcutaneous injection or implant, and the like. One ofskill in the art can readily determine appropriate dosage(s), treatmentregimens, etc. depending on the mode of administration employed.

For example, for oral administration, dosages in the range of about 1 upto 500 mg/kg body weight per day, depending on the disease state beingtreated, will be employed. Active compound can be administered in asustained release form, or in divided doses throughout the day. Fortopical delivery, in the range of about 0.05 mg up to 10 mg/kg bodyweight per day, depending on the disease state being treated, will beemployed. For injection modes of delivery, in the range of about 10 μgup to 2 mg/kg body weight per day, depending on the disease state beingtreated, will be employed. It should be emphasized, however, that dosagerequirements are variable and are typically individualized on the basisof the disease under treatment and the response of the patient. After afavorable response is noted, the proper maintenance dosage can bedetermined by decreasing the initial drug dosage in small increments atappropriate time intervals until the lowest drug dosage which willmaintain an adequate clinical response is reached. Those of skill in theart recognize that constant monitoring of the patient's condition isdesirable in regards to drug dosage.

In accordance with a particular embodiment of the present invention,there is provided a method for the treatment of a subject afflicted withacute promyelocytic leukemia, said method comprising administering tosaid subject an effective amount of a ligand which selectively interactswith retinoic acid receptors, in preference to retinoid X receptors. Ina preferred embodiment of the present invention, an effective amount ofa ligand which selectively interacts with RAR-α, relative to otherretinoic acid receptor subtypes (as well as retinoid X receptors), willbe employed. Ultimately, physicians will determine the particular dosageof the selective ligand which is most suitable. The selected dosage willvary depending upon the mode of administration employed, the particularcompound administered, the patient under treatment, and the particulardisease being treated.

In addition to the above-described applications of the inventiontreatment method, the method of the invention can be applied to theselective treatment of skin disorders such as acne, psoriasis,photodamage, and the like. For such applications, compounds whichselectively interact with RAR-α, relative to other retinoid receptors,are preferred.

It can be readily seen, therefore, that the invention treatment methodis useful in the treatment of a wide variety of disease states.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

EXAMPLES

A series of dose response curves were generated to determine theresponse of retinoic acid receptor-α, retinoic acid receptor-β, retinoicacid receptor-γ and retinoid X receptor-α upon exposure to retinoicacid, Compound I (i.e., the phenyl-naphthyl derivative), Compound II(i.e., the polyunsaturated carboxylic acid derivative), and Compound III(i.e., the amide derivative), and Compound IV (i.e., the benzophenonederivative).

Response to the various compounds was measured employing the "cis/transassay" as described by Evans et al., in U.S. Ser. No. 108,471 (filedNov. 30, 1988), the entire contents of which are hereby incorporated byreference herein. All assays were carried out employing CV-1 host cellsco-transformed with vectors encoding a receptor selected from RAR-α,RAR-β, RAR-γ, or RXR-α and a reporter vector.

The retinoic acid receptor-α was encoded by vector pRShRAR-alpha (seeU.S. Pat. No. 4,981,784, issued Jan. 1, 1991, the entire contents ofwhich are hereby incorporated by reference herein), retinoic acidreceptor-β was encoded by vector pRShRAR-beta (see Brand et al. inNature 332:850 (1988) and Benbrook et al. in Nature 333:669 (1988), theentire contents of which are hereby incorporated by reference herein),retinoic acid receptor-γ was encoded by vector pRShRAR-gamma (see U.S.Ser. No. 370,407, filed Jun. 22, 1989, the entire contents of which arehereby incorporated by reference herein), and retinoid X receptor-α wasencoded by vector pRShRXR-alpha (see U.S. Ser. No. 478,071, filed Feb.9, 1990, the entire contents of which are hereby incorporated byreference herein).

The reporter vector used in all experiments was TREp-ΔMTV-LUC, asdescribed by Umesono et al. in Nature 336:262 (1988), the entirecontents of which are hereby incorporated by reference herein.

EXAMPLE I Retinoic Acid Dose Response Curve

FIG. 1 presents the results of a dose response study carried out withretinoic acid as the ligand for each of the receptors: RAR-α, RAR-β,RAR-γ, and RXR-α.

At very low concentrations of retinoic acid (i.e., concentrations belowabout 1×10⁻⁹ ), each of the retinoid receptor subtypes is activated toapproximately the same extent. Similarly, at concentrations above about1×10⁻⁶, each of the retinoid receptor subtypes is activated toapproximately the same extent. Although, in the concentration range ofabout 1×10⁻⁹ -1×10 ⁻⁶, there is a readily discerned rank order potencyas follows:

    RAR-γ>RAR-β>RAR-α>RXR-α,

retinoic acid is seen to exert a substantial effect on each of theretinoid receptors tested. Administration of retinoic acid as atherapeutic agent is, therefore, likely to induce many hormone mediatedpathways, not just the pathway involved in the disease state to betreated.

EXAMPLE II Dose Response Curve For Compound I

FIG. 2 presents the results of a dose response study carried out withCompound I (phenyl-naphthyl derivative) as the ligand for each of thereceptors: RAR-α, RAR-β, RAR-γ, and RXR-α.

At very low concentrations of Compound I (i.e., concentrations belowabout 1×10⁻⁸), each of the retinoid receptor subtypes is activated toapproximately the same extent. However, at concentrations above about1×10⁻⁸, there is a readily discerned rank order potency as follows:

    RAR-γ≈RAR-β>>>RAR-α≈RXR-α.

Thus, Compound I could be used for the treatment of a disease statewhich involves RAR-γ and/or RAR-β, without perturbing pathways which areresponsive to RAR-α or the retinoid X receptor.

EXAMPLE III Dose Response Curve For Compound II

FIG. 3 presents the results of a dose response study carried out withCompound II (polyunsaturated carboxylic acid derivative) as the ligandfor each of the receptors: RAR-α, RAR-β, RAR-γ, and RXR-α.

At very low concentrations of Compound II (i.e., concentrations belowabout 1×10⁻⁹), each of the receptor subtypes is activated toapproximately the same extent. However, at concentrations above about1×10-8, the rank order potency is as follows:

    RAR-γ≈RAR-β≈RAR-α>>RXR-α.

Thus, Compound II could be used for the treatment of a disease statewhich involves a retinoic acid receptor, without perturbing pathwayswhich are responsive to the retinoid X receptor.

EXAMPLE IV Dose Response Curve For Compound III

FIG. 4 presents the results of a dose response study carried out withcompound III (amide derivative) as the ligand for each of the receptors:RAR-α, RAR-β, RAR-γ, and RXR-α.

At very low concentrations of Compound III (i.e., concentrations belowabout 1×10⁻⁹), each of the receptor subtypes is activated toapproximately the same extent. Similarly, at concentrations above about1×10⁻⁷, each of the receptor subtypes is activated to approximately thesame extent. However, at concentrations between about 1×10⁻⁹ and 1×10⁻⁷,the rank order potency is as follows:

    RAR-α>RAR-β≈RXR-α>RAR-γ.

Thus, Compound III could be used for the treatment of a disease statewhich involves RAR-α, while perturbing pathways which are responsive toother retinoid receptors to a much lesser extent.

EXAMPLE V Dose Response Curve For Compound IV

FIG. 5 presents the results of a dose response study carried out withcompound IV (benzophenone derivative) as the ligand for each of thereceptors: RAR-α, RAR-β, RAR-γ, and RXR-α.

At very low concentrations of Compound IV (i.e., concentrations belowabout 1×10⁻⁹), each of the receptor subtypes is activated toapproximately the same extent. However, at concentrations above about1×10⁻⁸, there is a readily discernible rank order potency as follows:

    RAR-γ≈RAR-β>>>RAR-α≈RXR-α.

Thus, Compound IV could be used for the treatment of a disease statewhich involves RAR-γ and/or RAR-β, without perturbing pathways which areresponsive to RAR-α or the retinoid X receptor.

While the invention has been described in detail with reference tocertain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

That which is claimed is:
 1. A method for the treatment of aretinoid-responsive disease state in a subject, said method comprisingadministering to said subject an effective amount of a ligand whichselectively interacts with the retinoid subtype associated with saidretinoid-responsive disease state, to a significantly greater extentthan with other retinoid subtypes.
 2. A method according to claim 1wherein said ligand which selectively interacts with the receptorsubtype associated with said retinoid responsive disease state isselected from RAR-α selective ligands, RAR-β selective ligands, RAR-γselective ligands, RXR-α selective ligands, RXR-β selective ligands,RXR-γ selective ligands.
 3. A method according to claim 1 wherein saidretinoid-responsive disease state is the result of translocation of aportion of a gene encoding a retinoid receptor and a portion of a secondgene; wherein the expression of said second gene is not ordinarilysubject to regulation by the retinoid which binds to said retinoidreceptor.
 4. A method according to claim 3 wherein saidretinoid-responsive disease state is APL.
 5. A method according to claim1 wherein said retinoid-responsive disease state is a skin disorder.